This application is a revised competitive renewal of our grant that is focused on understanding the mechanisms by which mutant huntingtin impairs mitochondrial function. In March 2007 I relocated to the University of Rochester specifically to join the Mitochondrial Research and Innovations Group (MRIG). This move has greatly enhanced our research endeavors that focus on understanding the basis for the mitochondrial dysfunction in Huntington's disease (HD). It also should be noted that during the last funding period we made several key discoveries and these findings serve as the basis for the present application. It is becoming increasingly clear that transcriptional dysregulation and mitochondrial impairment are key pathogenic processes in HD. Further there is clear evidence that the direct impairment of transcriptional processes by mutant huntingtin is likely a contributing event that causes the mitochondrial impairment. Two critically important outcomes of the impaired mitochondrial function are compromised calcium handling and energy metabolism, which eventually contribute to neuronal death in the disease process. Our long range goa/ is to fully elucidate the pathological processes by which mutant huntingtin impairs specific transcriptional events, the specific mitochondrial functions that are impaired and how these pathogenic events contribute to neuronal cell death in HD, The objective of this project is to identify the specific mitochondrial metabolic alterations due to the presence of mutant huntingtin, elucidate the transcriptional processes that are dysregulated in HD and thus result in these mitochondrial defects and determine if the can be pharmacologically ameliorated. The central hypothesis of this application is that mutant huntingtin disrupts key transcriptional processes that result in an impairment of mitochondrial function which subsequently contributes to neuronal dysfunction and death in HD. The rationale for these studies is that once it is known exactly how mutant huntingtin impairs mitochondrial function and thus contributes to neuronal dysfunction and death, then therapeutic targets for the treatment of HD can be identified. The objectives of this project will be accomplished through three specific aims that test the hypotheses: (1) that mutant huntingtin impairs the ability of mitochondria to appropriately maintain pH and regulate redox status and this contributes to the calcium handling defects that result in respiratory deficits and increased sensitivity to calcium-induced permeability transition pore opening, (2) mutant huntingtin resu lts in a downregulation of PPARy activity and this contributes to mitochondrial dysfunction, and (3) that activation of PPARy ameliorates mitochondrial dysfunction in a mouse HD model